CD4 depletion is one of the hallmarks of HIV infection in humans and simian immunodeficiency virus (SIV) infection in macaques. However, SIV infection in its natural primate host (i.e. sooty mangabeys) results in near normal levels of CD4+ T-cells and no signs of simian AIDS despite high plasma viral loads. A recent study from our laboratories has determined that the absence of CD4 depletion and AIDS symptoms in SIVsmm+ mangabeys corresponds with an absence of T cell activation and bystander apoptosis. The assessment of sooty mangabeys in this proposal will not focus on these naturally infected animals, but rather on a unique cohort infected via direct plasma transfer of SIVsmm from a naturally infected mangabey to six uninfected mangabeys. Following the plasma transfer, two mangabeys exhibited a decline in CD4+ T cell levels to below 100 cells/ul of blood that is also observed in lymph nodes. These levels have remained between 18 and 100 cells/ul of blood for the past 3 (mangabey SM1) and 2.5 (mangabey SM2) years. The goal of this proposal is to characterize the mechanisms behind the CD4 depletion in these SIVsmm-passaged mangabeys. Interestingly, a similar occurrence of CD4-low phenotype has recently been observed in 4 naturally infected mangabeys in the Yerkes colony indicating that this finding is not unique to the two SIVsmm passaged mangabeys. We hypothesize that an expansion of coreceptor usage, as has been observed in HIV infected patients, results in an increase in susceptible target cells and decreased T cell levels in these mangabeys. Importantly, we will first determine if SIVsmm-passage from a CD4-low mangabey to four additional mangabeys can recapitulate the CD4-low phenotype. Then, the potential mechanisms behind CD4 depletion will be assessed through the analysis of viral (coreceptor usage and viral sequencing) (Aim 1) and host immune factors (quantification of SIV-specific T cells) (Aim 2). These CD4-low SIVsmm+ mangabeys offer an important opportunity to assess the ability of a retrovirus to induce CD4 T cell depletion in the absence of indirect effects of activation induced apoptosis. It is not possible to separately assess the direct and indirect effects of a pathogenic HIV or SIV infection, therefore the CD4 depletion in SIV-infected mangabeys offers a unique opportunity to study the role of direct viral cytopathicity on CD4+ T cells.